Central to the pathogenic success of Mycobacterium tuberculosis (MTB) is its ability to persist within humans for long periods in a latent state, without causing any overt disease symptoms. Roughly one-third of the world population harbors latent MTB, greatly complicating efforts at tuberculosis control. A person with latent tuberculosis has about a 10 percent lifetime chance of developing active disease, and when such a person contracts HIV, the risk of developing reactivation TB increases to 8 - 10 percent per year. Hypoxic conditions within the human host are widely regarded as crucial for development of latent tuberculosis, but the MTB adaptive response to hypoxia is at present very poorly understood. The goal of this proposal is to define the MTB hypoxic response as it relates to latency and reactivation. The a-crystallin protein of MTB is powerfully induced by hypoxia and has been implicated in long-term survival. Alpha-crystallin will be used as a model system to determine the mechanisms by which oxygen tension control MTB gene expression. In addition, specific conditions in which Alpha-crystallin is necessary for achieving latency and reactivation will be determined. Finally, with Alpha-crystallin as an example, other proteins important for the adaptation to and from hypoxia will be identified and characterized. The result will be better tools to confront the threat to more than one billion persons with latent tuberculosis, millions of whom are now or will soon be co-infected with the human immunodeficiency virus, HIV.